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Bad Prognostic Markers in Acute Coronary
Syndromes Without Persistent
ST-Segment Elevation: Implications
of the Ischemic Event Chosen as End Point

Bono, Julio O; Fernández Cid, Gerardo; Ramos, Hugo;
and Investigators of the Multicenter Study TROTESATI
organized by the Coronary Care Committee
of the Argentine Society Intensive Care Unit.

Buenos Aires. Argentina

SUMMARY
Introduction: Recently, the Score TIMI, added to the seric markers, was proposed to establish prognosis in patients with Acute Ischemic Syndromes (AIS) without persistent ST-segment elevation.
Objective: To analyze the independent prognosis value, in our series of patients with AIS from the prognosis markers (PM) of TIMI and of TropT Sensitive, on hospital ischemic event (HIE) in general and on each event in particular.
Methods: It's a prospective multicentric study of 405 patients admitted to the study with Trop T Sensitive in patients with AIS from 1/12/1999 to 1/2/ 2001. It was considered the combined result of two TT in the admission. The HIE considered were: Pump Failure (PF), Mortality (M), acute MI Q and not Q (MI). The PM analyzed were: TT, CPK, Age >65 years old, diabetes (Dbt), ST-segment elevation, ST-segment depression, changes in ST (STc), T-wave changes (Tw), background in the use of AAS, pain > 30 min. (P), 3 or more Risk Factors (RF). Univariate analysis of association between PM with HIE, PF, M and MI by Chi quadrate or Fisher Test with estimation of Odds Ratio (OR) and respectively CI 95%. Multivariate analysis, equal associations, multiple logistic regression analysis (MLR) with Stepwise selection technique and estimation of Exp-Beta as an approximation to OR pondered (multivariate or adjusted) and CI 95% respectively.
Results: TT, CPK, age and STc were the independent PM of higher risk for HIE either in the univariate (OR=8.5, 2.4, 1.6 and 1.6 respectively, all of them with CI 95% > 1.00) or in the multivariate (Exp-beta= 6.2, 2.3, 1.9 and 1.8 respectively, all of them with CI 95% >1.00). To prognosis of M or PF, age, Dbt, and STs (Exp-beta= 7.5, 5.6, y 3.1) were the only significative ones in MLR. For the MI, the TT, CPK and STc (Exp-beta= 19.9, 2.8 and 2.0) were independent and significant.
Conclusion: The PM vary according to the type of HIE considered. TT was the most significant PM for MI, meanwhile age and Dbt were for M and PF.

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INTRODUCTION
   One of the most important things in the diagnostic area is to classify the patients with ACS in an appropriate way within a risk category for subsequent events. The appropriate risk stratification provides important information in the evaluation and treatment with scientific support and also, allows to choose among the different levels of complexity of clinical follow up, the appropriate one for each risk level and the moment of discharge in patients with low risk.(1-4)

   The risk stratification has to be early at admission, simple and practical in its application and preferably by using routine clinical data at hand in the moment of hospital admission.(5,6)

   Serum cardiac markers used together with background information, physical examination, EKG of 12 derivations, also useful in the diagnostic of AMI, would be among the most important early and routine clinical data needed at admission that allow to evaluate the risk of subsequent cardiac events and to evaluate the algorithm and treatment of patients with ACS.(7)

   In order to evaluate the benefits of each variable within a system that requires an average prognostic value, we proposed different multivariate models in the risk stratification in patients with ACS with or without persistent ST-segment elevation.(6, 8-14.)

   In this study, we tried to identify the independent prognostic factors in a series of patients with UA so as to predict the IE and in-hospital M. Besides, we tried to evaluate the predictive value of each factor on each IE that is part of the final combined events, so as to determine the implications of the event to be predicted in the selection and validity of a specific prognostic factor.

MATERIAL AND METHODS
   We selected 397 out of 406 patients with unstable angina from the data of patients recruited for the multicenter study TROTESATI (8/16/1999 to 3/30/2001) and we evaluated the predictive value of a quick test of cardiac Troponin T (TROPT®) in patients with UA. 21 national centers, 2 Coronary Units (n= 204) and 19 Intensive Unit Care (IUC) (n= 201) took part in the study.

   Patients with UA with and without changes T/ST-segment in EKG at admission with previous coronary disease were included.

   The fatal and non fatal IE considered were: M, PF, AMI Q and non Q and recurrent angina. We did not include as IE the mortality by other causes, like Stroke or peripheral vascular disease. In all the cases, the death cause and the rest of IE were followed by professionals and cardiologists without any relation to the study.

   Among the prognostic factors included were: age (>65 years old or younger), ST-segment depression in EKG, ST-segment elevation, changes in ST, changes in T-wave, the professional's interpretation of EKG (with ischemic changes, normal or non conclusive), angor duration, prior use of aspirin for more than one week before admission, the presence of three or more cardiovascular risk factors (tobacco, dislipemia, diabetes, hypertension, stress, obesity), the presence of diabetes with or without another associated factor, diabetes as the only risk factor, quick test of Troponin T and CPK.

   The worst value of EKG within the first 12 hours of the onset of pain was taken. Troponin T (TROPT®), CPK / CK-MB, were evaluated immediately after admission and repeated within the next 6 hours in case the results were negative.

   Statistical analysis: The univariate analysis was developed by contrasting the degree of the exposition to a particular prognostic factor among groups with an IE of interest. The proportions were contrasted by Chi square with correction of Yates by defect or Exact Fisher Test if necessary. The rate of probabilities of exposition (Odds Ratio) was calculated among groups formed by the presence or absence of the event of interest and the bands min-max were determined to form the respective CI (95%)

   For the multivariate analysis, Logistic Multiple Regression (LMR) was used with technique of conditional selection (Forward- Stepwise) including all the probable prognostic factors in one step and changing the dependent variable (class event or combined event) to make the different prognostic models. The criteria for selection was P<0.05 in the improvement of Chi square for the admission of variables to the model and P>0.10 for the exclusion. Of each model we showed the final Chi square (x2), P, R2%; % of Chi square that corresponds to the most significant variable, discrimination of the model to a standard cutoff in 50 % of probability with determination of sensibility (S) and specificity, Hosmer-Lemeshow (BA-HL) test. These results are shown below table 2.

   An alfa value of 5 % (P<0.05) was determined for statistics signification, or a CI 95% that did not include the unit when the results are shown in terms of OR.

RESULTS
   57,4 % of the series was male sex, average age 63± 12.3 years old, 49.6% with previous coronary disease (AMI 23.4%, PTCA 10.6 %, CABG 6.5%, stable angina 15.6%), 83.5% angor with changes in EKG at admission, 56.9% as angor of new onset.

   The description of independent variables (prognostic factors) and dependent ones (IE in hospital) are shown in Table 1. We point out that 46.3% of the series was >65 years old, 72.8% showed an EKG at admission with signs of ischemia according to the professional criteria, 58.5% had previously suffered angor >30 minutes, 41.3% had used aspirin for more than one week before admission and 27.7 % had a positive TROP combining the result of two tests.

   130 patients (32.7%) suffered one or more ischemic event while in hospital (combined event). The incidence of AMI Q and Non Q was 18.64 % (n= 74), followed by the incidence of recurrent angina in 12.1% of the patients.

UNIVARIATE ANALYSIS
   In the univariate analysis, the most significant prognostic markers of combined events were: age >65 years old (OR 1.63), ST-segment depression (1.60), changes in ST (1.97), changes in T-wave (0.64), EKG with ischemia (2.17), elevated CPK at admission (2.37) and TROPT (+) (8.48 CI 95% 5.2-13.9). In figure 1 the estimation of OR and its respective CI 95% are shown, and the line that represents CI 95% must not include or touch the unit (OR 1.0) in order to be considered a significant factor.

   As far as mortality (figure 2), the factors were age >65 years old (OR 9.68), ST-segment elevation (4.94), EKG with ischemia signs (1.03) and Diabetes as the only risk factor (7.11) or associated to other factors (6.44). The significant factors for pump failure were: age >65 years old (OR 8.07 CI 95% 1.8-36.3), Diabetes as the only risk factor (6.57 CI 95% 1.7-25.9) or associated to other factors (2.80 CI 95% 1.0-7.9).

   During hospital stay, in the prognostic of AMI Q and non Q were significant the ST-segment elevation (OR 2.98), changes in ST (2.71), EKG with ischemia signs (2.46), Diabetes (1.75), elevated CPK (2.71), TROPT (+) (23.4 CI 95% 12.2-45.0) and prior aspirin as protector (OR 0.58 CI 95% 0.34-097) (Figure 3). On the other hand, in the prognosis of the recurrent angina the ST-segment elevation showed a paradoxical protective result (OR 0.23) and the prior aspirin use increased the risk (OR 1.99) (Figure 4).


MULTIVARIATE ANALYSIS
   The result of the multivariate analysis for each event or combined event is shown in table 2.

   In the prognostic of combined ischemic events (table 2), TROPT (+) was the most significant independent prognostic factor (OR 6.22 CI 95% 3.6-10.7), followed by elevated CPK (OR 2.34), age >65 years old and the changes in the ST-segment (OR 1.82). This result showed that 56.9% patients with one or more events versus 13.5% without events, had TROPT (+) (P<0.0000001), or also, from the incidence, patients TROPT (+) showed an incidence of combined events of 67.3% versus 19.5% in TROPT (-). 38.9 % versus 28.1 % of >65 years old and younger respectively suffered some event (P<0.05), the 40.8% versus 25.9 % with and without changes in ST (P<0.005).

   In the prognostic factors for pump failure and mortality, age >65 years old was the most significant independent factor (OR 7.53 CI 95% 2.2-26.4) followed by diabetes as the only risk factor (OR 5.61) and ST-segment elevation (OR 3.07). 10.3% versus 1.5% of >65 years old with respect to the youngest, died or suffered pump failure (P< 0.001), 23.5% versus 4.5% of those patients with or without Diabetes as the only risk factor (P<0.01)

   In AMI, TROPT (+) is again the most significant independent prognostic factor (OR 19.9 CI 95% 9.9-40.0), followed by CPK (OR 2.83) and the changes in ST-segment (OR 2.01). The incidence of AMI Q and non-Q in patients TROPT (+) was 54.5% versus 4.9% with TROPT (-) (P<0.0000001), 32.1% versus 14.8% with and without elevated CPK at admission (P<0.01) and 26.6% versus 11.8% with and without changes in the ST-segment (P<0.001).

   None of the proposed variables was significant in the multivariate analysis to identify independent prognostic factors for episodes of recurrent angina during hospital stay, including the phenomenon of risk observed with the chronic previous aspirin use; nevertheless, the univariate incidence of recurrent angina was 16.5% versus 9.0% with and without prior use of aspirin respectively (P<0.05)

DISCUSSION
   The baseline clinical characteristics would not be enough to stratify the risk of combined events with the risk variability needed in the consecutive stratums, 15 although they would allow identifying patients with very low risk.(14)

   On the other hand, it is well established the value of ST-segment deviation and T-wave in the EKG at admission as an independent predictor of high risk patients with ACS.(13, 16-18) Unfortunately, a lot of the initials EKG are not conclusive or do not show ischemic changes.

   With the introduction of the new serum markers, particularly the cardiac Troponin T, that have proved to demonstrate a high sensibility, diagnostic and prognostic specificity in large series of patients with unstable angina, (21-35) the investigators started to adopt them as part of the design of new stratification systems, or to adapt the established clinical classifications such as the Braunwald ones.(36)

   Even though an abnormal value of Troponin at any moment after an angor has an elevated predictive value of an unfavorable cardiac event, the best strategy it will always be to evaluate it together with CK-MB, EKG and clinical findings.(38)

   Such strategy is one of the objectives in the consensus for a prognostic system scientifically proved that joins all the results of those variables, or only the most significant ones, in order to classify the patient in the appropriate risk stratum.

   Thus, the univariate analysis is an initial way of evaluation on the potential prognostic value of a specific variable, nevertheless, according to the complex baseline state of patients with ACS, the multivariate analysis that adjusts multiple prognostic variables at the same time, provides a more specific way of risk stratification.(8, 18,39,40)

   Several multivariate models for risk stratification in patients with ACS with or without persistent ST-segment elevation have been proposed. (6, 8-14,41). Among those that evaluate prognosis in patients with UA, it stands out a model recently published, very simple in its application, composed by 7 factors of easy identification during admission for prognosis in mortality and non fatal AMI, called TIMI Risk Score.(8)

   In our experience, we could not evaluate the 7 factors of TIMI Risk score, as we would wish to do, since it was published after the recruitment and evaluation of patients in our series, then we did not have some variables and others are different in their definition. In spite of the partial coincidence, we could prove that age >65 years old, St desviation in EKG and elevation of serum markers (TROPT (+)) are also prognostic factors for combined events in our series. On the contrary, prior aspirin use, that appeared to be significant only in the univariate analysis, and three or more risk factors for coronary disease, were not factors with independent significance. The significant coronary stenosis and severe angina symptoms were not analyzed.

   The general tendency was to form as a final point a variable of a "combined or complex events" that included all the manifestations of ischemia at the same time, and from then, to be able to identify significant prognostic factors for those events. The true degree or severity of the ischemia and the underlying mechanisms might be disguised and there is a risk of choosing the wrong therapeutical alternative by assuming that it is effective with all the events at the same time (even with pump failure and other non coronary ischemia manifestations added to the combined events). That is to say, it could wrongly be believed that a high risk patient for combined events has similar probability of developing cardiovascular death as AMI Q or recurrent angina or pump failure during follow up.

   Our results suggest that the selection of events that will be part of the final point of "combined events" might generate a slant in the appreciation of the true prognostic value of a factor, marker or variable. So, we should be cautious when evaluating the value of a prognostic factor, mainly if it will have implications in the therapeutical decisions. It would be recommended to analyze the value of each prognostic factor on each clinical event of interest separately before analyzing it over a final point of combined events. Thus, the true prognostic value could be appreciated better and the underlying mechanisms of the particular event could be explained as well as determine the impact that it will have on its prognostic variable the modification of the event or the events to be predicted.

   It is not surprising that Troponin T outcomes as the most significant independent prognostic factor when the final point is AMI (fatal and non fatal), since the increasing values of cardiac Troponin correlate simultaneously with the severity of the coronary disease by angiographic findings and with the prognostic of patients with ACS.(22, 43,44) It would be also reasonable that age appears as a prognostic factor of mortality, even proved in other international studies with Argentine patients, 41 since it can be assumed it correlates in an increasing way to a greater sensitivity and clinical inestability. The Troponin Test and/or age would have more or less prognostic value or interaction degree according to AMI, death and even the fatal AMI event among the combined ones.

   In our case, TROPT in itself has a sensibility of 81.1% and a specificity of 84.5% in the AMI prognosis in our series, and when it is associated to the outcomes of CPK and changes of ST-segment (AMI Q and non Q) and adjusted to the cutoff, it is possible to raise the sensibility to a 86.4% keeping a 81% specificity. The profit is only a 5.4%. In spite of this, TROPT did not show a significant prognostic value for cardiovascular mortality and recurrent angina.

   According to lots of studies, a stable parameter in the prognostic of combined events is the condition of the ST-segment and /or T-wave in the EKG at admission.(6, 8-13,16-18).

   The effectiveness in the use of combined Troponin (6- 12 hours) with the changes in the St-segment of EKG within the first 12-24 hours as tools of risk stratification for AMI and/or cardiovascular mortality has been well-established.(22, 45-50) our results agree with this, especially in the prognostic of AMI in patients admitted with UA.

   Our model of combined events had the same factors as the model that predicts AMI, but it adds age as an independent predictor.

   AMI is the principal event in our centers and the main component of combined events (57% of the patients with events) where TROPT is sensible and specific and when age is added, then, we are including the most significant factor in the prognostic of mortality, pump failure and recurrent angina. It is necessary to point out that with this combined focus, we could wrongly assume that a TROPT (+) patient is a high risk one for pump failure or recurrent angina in a similar way it would be for AMI.

   An example on how the events chosen as End Point and the effect of combining them, modify in an important way the prognostic value of the factors, can also be observed in the outcomes of the study ESSENCE.14 In this study, a group of factors or variables are common in the prognostic of the "triple final point" (death, AMI and recurrent angina) and in the "double final point" (death and AMI) but with unequal signification, meanwhile another subgroup of factors were common only for the triple final point. When recurrent angina is eliminated from the model, it appears as evident that a subgroup of prognostic factors respond particularly in the presence of the triple point instead of the double one, and at the same time the common factors and the model in general improved the prognostic value only of AMI and mortality.

   This helps to explain why in some series, the prior use of aspirin may result a factor of bad prognosis (univariate / multivariate) for combined events. If we analyze the composition of the combined events in these studies, it would be noticeable that recurrent angina is part of the combined events and there may be a high frequency of it and/or a low frequency of fatal AMI Q and non Q. García Dorado and et al's report, 51 among others, 52 contributes to understand this phenomenon.

   In our series, prior use of aspirin was a univariate significant factor that predicts recurrent angina, and if our series had a relatively high incidence of this complication, it would outcome in a prognostic factor of combined events with the consequent slant.

   Like aspirin, other prognostic factors of AMI showed an opposed or unexpected prognostic effect for recurrent angina (example: TROPT). This could be in this way because of the polarization AMI-recurrent angina in the ischemia gradient, and then, every factor that indicates a probable development of AMI may be at the same time a factor in the opposite sense for recurrent angina and vice versa. (Example: aspirin as indicator of good prognosis for AMI but a risky one for recurrent angina)

CONCLUSIONS
   As in other studies on this subject, in our series of patients with unestable angina, the presence of one or more ischemic events shown during evolution (considered altogether as a compound final point) it correlates with simple prognostic variables such as age >65 years old, the deviations of ST-segment in EKG and the raise of serum markers (in our case TROPT (+) and CPK). Nevertheless, a specific factor does not keep an equal prognostic value for all the ischemic events that form the combined events.

   Our outcomes suggest that the selection of events that will make up the combined events may generate a slant in the appreciation of the prognostic value of a specific factor or predictable variable. The direction of this slant might have straight relation to the predominant event and/or the degree of polarization in the clinical manifestation of the ischemia (AMI Q/ recurrent angor) in the analyzed series.

 

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
Scientific Committee
President
Dr. Armando Pacher
Technical Committee - CETIFAC
President
fgaro@fac.org.ar
fgaro@satlink.com
rbretal@fac.org.ar
rbretal@netverk.com.ar
apacher@fac.org.ar
apacher@satlink.com

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